Background: We previously reported up-regulation of tigarb (the zebrafish orthologue? of human TIGAR, TP53-Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms. Materials and Methods: TIGAR Immunohistochemistry using a range of antibodies was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n=10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n=4 control, 4 PD, and 4 dementia with Lewy bodies). Results: TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections confirmed the presence of TIGAR alongside alphasynuclein in these LB and Neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I. Conclusions: TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA ID Sex Diagnosis Age (years) P2/10 F sPD 82 P54/11 M sPD 80 P89/10 M sPD 77
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